Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia.
Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia.
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DOI：
10.1038/nm.3936
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发表时间：
2015-10
期刊：
影响因子：
82.9
通讯作者：
Steidl, Ulrich
中科院分区：
文献类型：
--
作者：
Will, Britta;Vogler, Thomas O.;Narayanagari, Swathi;Bartholdy, Boris;Todorova, Tihomira I.;Ferreira, Mariana da Silva;Chen, Jiahao;Yu, Yiting;Mayer, Jillian;Barreyro, Laura;Carvajal, Luis;Ben Neriah, Daniela;Roth, Michael;van Oers, Johanna;Schaetzlein, Sonja;McMahon, Christine;Edelmann, Winfried;Verma, Amit;Steidl, Ulrich
Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reduction of PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in 35% reduction of PU.1 expression, was sufficient to induce myeloid biased preleukemic stem cells and subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1 cooperating transcription factor, Irf8. Strikingly, we found significant molecular similarities with human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor that commonly occurs in human disease is sufficient to initiate cancer development and provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.
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DOI：
10.1084/jem.20050075
发表时间：
2005-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dakic A;Metcalf D;Di Rago L;Mifsud S;Wu L;Nutt SL
通讯作者：
Nutt SL
影响因子：
64.5
作者：
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通讯作者：
Delwel, Ruud
影响因子：
82.9
作者：
通讯作者：
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影响因子：
20.3
作者：
Bonadies，Nicola;Pabst，Thomas;Mueller，Beatrice U.
通讯作者：
Mueller，Beatrice U.
DOI：
10.1084/jem.20111490
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dykstra B;Olthof S;Schreuder J;Ritsema M;de Haan G
通讯作者：
de Haan G